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2.
Acta Pharm Sin B ; 9(4): 769-781, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31384537

RESUMO

Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus (HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein (GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A (VAP-A) in competition with the HCV NS5A, causing an interruption of the complex formation between VAP-A and HCV NS5A. As the formation of VAP-A/NS5A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents (DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.

3.
Eur J Pharmacol ; 853: 111-120, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30902657

RESUMO

Farnesoid X receptor (FXR) agonists play important regulatory roles in bile acid, lipid and glucose metabolism in vitro and in vivo. Thus, FXR agonists exhibit potential therapeutic effects on metabolism-related diseases that are associated with extrahepatic manifestations induced by hepatitis C virus (HCV) infection. This study investigated the effect and mechanism of FXR agonist GW4064 against HCV in vitro to explore the potential application of FXR agonists. Results showed that GW4064 and other FXR agonists have potent antiviral activity against HCV in Huh7.5 cells. GW4064 down-regulated the expression of scavenger receptor class B type I protein via FXR and thereby indirectly inhibited HCV entry into cells, leading to interruption of HCV life cycle. GW4064 also exhibited synergistic anti-HCV effect with known direct-acting antiviral agents (DAAs) used in the clinic and remained sensitive to DAA-resistant HCV mutations. Therefore, FXR agonists are also a kind of antiviral agent, and might be helpful in treatment of HCV-induced hepatic and extrahepatic manifestations.


Assuntos
Regulação para Baixo/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepacivirus/fisiologia , Isoxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Depuradores Classe B/genética , Internalização do Vírus/efeitos dos fármacos , Antivirais/farmacologia , Linhagem Celular , Sinergismo Farmacológico , Hepacivirus/genética , Humanos , Mutação , RNA Viral/biossíntese , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Virais/metabolismo
4.
Int J Immunopathol Pharmacol ; 33: 2058738418820743, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30791797

RESUMO

Abnormal expression of long noncoding RNAs (lncRNAs) is closely associated with the pathogenesis of multiple malignancies, and lncRNA small nucleolar RNA host genes (SNHGs) play critical roles in tumor progression. However, the mechanism by which SNHG3 contributes to osteosarcoma (OS) remains elusive. The association between SNHG3 expression and the clinicopathological characteristics in OS patients was analyzed using the TCGA (The Cancer Genome Atlas) dataset. Cell viability and colony number were estimated by MTT and colony formation assays. MiR-196a-5p-specific binding with SNHG3 or HOXC8 was confirmed by the luciferase report assay. As a result, the expression of SNHG3 was dramatically increased in OS tissue as compared with the adjacent normal tissues. High expression of SNHG3 was associated with tumor size and acted as an independent prognostic factor of poor survival in OS patients. Knockdown of SNHG3 inhibited cell viability and colony formation, but its overexpression reversed these effects. SNHG3 was further identified to act as a sponge of miR-196a-5p, which counteracted the tumor-promoting effects caused by SNHG3 in OS cells. The expression of miR-196a-5p had a negative correlation with SNHG3 and the poor survival in OS patients. In conclusion, lncRNA SNHG3 promoted cell growth by sponging miR-196a-5p and indicated a poor prognosis in OS patients.


Assuntos
Proliferação de Células/genética , Sobrevivência Celular/genética , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Longo não Codificante/genética , Adolescente , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Prognóstico
5.
Appl Opt ; 57(19): 5399-5404, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30117832

RESUMO

This paper proposes a multi-view three-dimensional display method based on a scanning imaging system with the light-intensity characteristic recorded by an improved flatbed scanner. Within the effective scanning depth of the imaging sensor, two transmission images are each simultaneously acquired by two linear CCD modules with different focal planes. Then the phase gradient information of the target can be obtained by an appropriate retrieval algorithm. Further, the multi-view three-dimensional effect is presented through dynamic angles of view. Theoretical analysis of this method is discussed, and experiments are carried out by building a scanner. The experiment results are presented with an algae specimen and transparent beads. We hope this method can be applied to present the three-dimensional effect of objects of flat translucent multilayer structure with a wide field of view.

6.
Int J Mol Med ; 40(6): 1792-1802, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29039494

RESUMO

The hepatitis C virus (HCV) infection is associated with various extrahepatic manifestations, which are correlated with poor outcomes, and thus increase the morbidity and mortality of chronic hepatitis C (CHC). Therefore, understanding the internal linkages between systemic manifestations and HCV infection is helpful for treatment of CHC. Yet, the mechanism by which the virus evokes the systemic diseases remains to be elucidated. In the present study, using gene set enrichment analysis (GSEA) and signaling pathway impact analysis (SPIA), a comprehensive analysis of microarray data of mRNAs was conducted in HCV-infected and -uninfected Huh7.5 cells, and signaling pathways (which are significantly activated or inhibited) and certain molecules (which are commonly important in those signaling pathways) were selected. Forty signaling pathways were selected using GSEA, and eight signaling pathways were selected with SPIA. These pathways are associated with cancer, metabolism, environmental information processing and organismal systems, which provide important information for further clarifying the intrinsic associations between syndromes of HCV infection, of which seven pathways were not previously reported, including basal transcription factors, pathogenic Escherichia coli infection, shigellosis, gastric acid secretion, dorso-ventral axis formation, amoebiasis and cholinergic synapse. Ten genes, SOS1, RAF1, IFNA2, IFNG, MTHFR, IGF1, CALM3, UBE2B, TP53 and BMP7 whose expression may be the key internal driving molecules, were selected using the online tool Anni 2.1. Furthermore, the present study demonstrated the internal linkages between systemic manifestations and HCV infection, and presented the potential molecules that are key to those linkages.


Assuntos
Hepacivirus/fisiologia , Hepacivirus/patogenicidade , Hepatite C/metabolismo , Hepatite C/fisiopatologia , Interações Hospedeiro-Patógeno/fisiologia , Transdução de Sinais/fisiologia , Algoritmos , Linhagem Celular , Biologia Computacional , Infecções por Escherichia coli , Regulação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Transcrição
7.
Biomed Res Int ; 2017: 1236801, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28904942

RESUMO

Use of direct-acting antivirals sometimes causes viral drug resistance, resulting in inefficiency in treated patients in real-world practice. Therefore, how to rapidly and accurately evaluate drug resistance is an urgent problem to be solved for rational use and development of antivirals in the future. Here, we aim to develop a new method by which we can evaluate easily but effectively whether a drug will still be efficient in the future treatment in infectious hepatitis C virus cell culture system. HCV-infected Huh7.5 cells were treated with drugs and the culture supernatants were replaced with fresh culture media containing the same drugs at 24 hours. The supernatants were harvested at 48 hours and incubated with naïve Huh7.5 cells. Intracellular HCV RNAs or proteins in the newly infected cells were extracted and analyzed at 48 hours or longer. Results showed that after being treated with telaprevir mutant viruses were easily detected which were resistant to telaprevir, while after being treated with sofosbuvir drug-resistant viruses did not emerge. In conclusion, the new method is simple and quick but accurate to evaluate whether a drug will be still efficient in the forthcoming therapeutic regimen and whether drug resistance will occur after long-term treatment with drugs.


Assuntos
Farmacorresistência Viral/genética , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Antivirais/farmacologia , Linhagem Celular , Farmacorresistência Viral/efeitos dos fármacos , Genótipo , Hepacivirus/patogenicidade , Hepatite C/virologia , Humanos , Oligopeptídeos/farmacologia , Proteínas não Estruturais Virais/genética
8.
Bioorg Med Chem Lett ; 27(9): 1962-1966, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28320615

RESUMO

Twenty-two novel 12N-substituted matrinic ethanol derivatives were synthesized and evaluated for their antiviral activities against HCV taking compound 1 as the lead. The SAR study indicated that the shortening of the 11-butyl chain to ethyl chain did not affect the activity significantly. Out of the target compounds, matrinic ethanol 6a demonstrated a potential anti-HCV effect with an EC50 value of 3.2µM and a SI value of 96.6. The free hydroxyl arm in 6a made it possible as a parent structure to prepare pro-drug for the potential application in HCV treatment. This study provided powerful information on further strategic optimization and development of this kind of compounds into a novel family of anti-HCV agents.


Assuntos
Alcaloides/química , Alcaloides/farmacologia , Antivirais/química , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Quinolizinas/química , Quinolizinas/farmacologia , Alcaloides/farmacocinética , Animais , Antivirais/farmacocinética , Linhagem Celular , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/farmacologia , Etanol/análogos & derivados , Etanol/farmacocinética , Etanol/farmacologia , Hepacivirus/crescimento & desenvolvimento , Hepatite C/tratamento farmacológico , Humanos , Quinolizinas/farmacocinética , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
Sci Rep ; 6: 21808, 2016 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-26898231

RESUMO

The cluster of differentiation 36 (CD36) is a membrane protein related to lipid metabolism. We show that HCV infection in vitro increased CD36 expression in either surface or soluble form. HCV attachment was facilitated through a direct interaction between CD36 and HCV E1 protein, causing enhanced entry and replication. The HCV co-receptor effect of CD36 was independent of that of SR-BI. CD36 monoclonal antibodies neutralized the effect of CD36 and reduced HCV replication. CD36 inhibitor sulfo-N-succinimidyl oleate (SSO), which directly bound CD36 but not SR-BI, significantly interrupted HCV entry, and therefore inhibited HCV replication. SSO's antiviral effect was seen only in HCV but not in other viruses. SSO in combination with known anti-HCV drugs showed additional inhibition against HCV. SSO was considerably safe in mice. Conclusively, CD36 interacts with HCV E1 and might be a co-receptor specific for HCV entry; thus, CD36 could be a potential drug target against HCV.


Assuntos
Antivirais/farmacologia , Antígenos CD36/genética , Hepacivirus/efeitos dos fármacos , Ácidos Oleicos/farmacologia , Receptores Virais/genética , Succinimidas/farmacologia , Ligação Viral/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/farmacologia , Antígenos CD36/antagonistas & inibidores , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Sinergismo Farmacológico , Regulação da Expressão Gênica , Células HEK293 , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Hepatócitos/virologia , Interações Hospedeiro-Patógeno , Humanos , Camundongos , Oligopeptídeos/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptores Virais/antagonistas & inibidores , Receptores Virais/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Transdução de Sinais , Testes de Toxicidade Aguda , Transgenes , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Replicação Viral
10.
Yao Xue Xue Bao ; 51(6): 913-8, 2016 06.
Artigo em Chinês | MEDLINE | ID: mdl-29879344

RESUMO

The level of intracellular keratin 8(KRT-8) is associated with liver diseases, whose expression is increased in hepatitis C virus(HCV)-infected patients with hepatocarcinoma and in cultural cells infected with HCV. However, it is not clear whether KRT-8 will impact HCV replication. In this paper, the HCV replication was analyzed in response to high expression and silence of KRT-8. The inhibitory activities against wild-type and mutant HCV were also analyzed by silence of KRT-8 or combined with known anti-HCV drug telaprevir. Results showed that the protein level of KRT-8 was increased in proportion with the HCV replication. The high expression was found to facilitate HCV replication, while the silence of KRT-8 was able to inhibit HCV replication and enhanced the anti-HCV activity of telaprevir. It also inhibited A156 T and D168 V mutant HCV, which are resistant to protease inhibitors. These results suggest that KRT-8 is a co-factor for HCV replication. Down-regulation of KRT-8 can inhibit wild type and mutant HCV replication to enhance the anti-HCV activity of known anti-HCV drugs. Therefore, KRT-8 may be a new target in the development of anti-HCV agents.


Assuntos
Hepacivirus/fisiologia , Queratina-8/metabolismo , Replicação Viral , Antivirais/farmacologia , Carcinoma Hepatocelular/virologia , Células Cultivadas , Replicação do DNA , Humanos , Oligopeptídeos/farmacologia , Inibidores de Proteases/farmacologia
11.
PLoS One ; 10(3): e0121608, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25811715

RESUMO

Human APOBEC3G (hA3G) is a cytidine deaminase that restricts replication of certain viruses. We have previously reported that hA3G was a host restriction factor against hepatitis C virus (HCV) replication, and hA3G stabilizers showed a significant inhibitory activity against HCV. However, the molecular mechanism of hA3G against HCV remains unknown. We show in this study that hA3G's C-terminal directly binds HCV non-structural protein NS3 at its C-terminus, which is responsible for NS3's helicase and NTPase activity. Binding of hA3G to the C-terminus of NS3 reduced helicase activity, and therefore inhibited HCV replication. The anti-HCV mechanism of hA3G appeared to be independent of its deamination activity. Although early stage HCV infection resulted in an increase in host hA3G as an intracellular response against HCV replication, hA3G was gradually diminished after a long-term incubation, suggesting an unknown mechanism(s) that protects HCV NS3 from inactivation by hA3G. The process represents, at least partially, a cellular defensive mechanism against HCV and the action is mediated through a direct interaction between host hA3G and HCV NS3. We believe that understanding of the antiviral mechanism of hA3G against HCV might open an interesting avenue to explore hA3G stabilizers as a new class of anti-HCV agents.


Assuntos
Citidina Desaminase/metabolismo , Hepacivirus/fisiologia , Hepatite C/metabolismo , Hepatite C/virologia , Interações Hospedeiro-Patógeno , Proteínas não Estruturais Virais/metabolismo , Replicação Viral , Desaminase APOBEC-3G , Linhagem Celular , Hepatite C/patologia , Humanos , Espaço Intracelular/metabolismo , Modelos Moleculares , Ligação Proteica , Mapas de Interação de Proteínas
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